The long term objective of these studies is to examine the feasibility of vaccinating against human immunodeficiency virus (HIV) using genetically engineered viral polypeptides. As part of this project, we will be evaluating the effects of sequence variation within the viral envelope gene on immune responses to genetically engineered HIV glycoproteins. There are a number of observations that points to gp120, the larger external glycoprotein of HIV, as a logical candidate subunit vaccine for this virus. Gp120 binds to CD4, the putative HIV receptor and also elicits HIV neutralizing antibodies in experimental animals. However, most of the sequence variation within the HIV env gene is the gp120 coding region. This variation appears to have a profound effect on humoral immunity to gp120 since the antibodies elicited by gp120, both fully glycosylated and non-glycosylated forms, appear to be strain specific; they exhibit a preference for neutralizing the strain from which the antigen was derived. We are proposing to molecularly clone a series of biologically distinct HIV isolates and produce glycosylated and non-glycosylated gp120 polypeptides from each strain. Humoral and cellular immune responses of experimental animals to these polypeptides will be examined. We will characterize the strain specificity of the elicited antibodies in an in vitro neutralization assay and T-cell responses in various in vitro lymphocyte proliferation assays. We will be testing the hypothesis that there are HIV subgroups that can be identified on the basis of immune responses to their gp120 polypeptides. This proposal is part of a program project with a primary goal of comparing various strategies for vaccinating against HIV. In addition to our own studies of immunity to HIV envelope antigens, we will also be providing molecularly cloned HIV DNA and genetically engineered HIV antigens to other participants in the program project for their proposed research. Collectively, we hope to devise a rational approach to designing an HIV vaccine.